My career goal with this application is to study how laboratory and clinical trial research techniques be merged with my training in neuroendocrinology to develop new treatments for substance addictions. The Division on Substance Abuse at Columbia University has been and would be a stimulating environment to carry out the pilot study proposed in this K23. Its goal is to test if mifepristone, a central and peripheral glucocorticoid receptor (GR) antagonist, can decrease relapse to cocaine use and stress sensitivity in cocaine dependent patients. Stress is implicated in cocaine abuse in clinical surveys and reports, and measures to reduce the perpetuating effect of stress on cocaine use could represent a new treatment avenue. Laboratory models of stress in humans have reliably reproduced measurable stress parameters in cocaine dependent individuals; moreover, stress induced cocaine cravings have been correlated with a higher risk of relapse. We hypothesize that by blocking the GR with mifepristone, the risk of relapse will diminish. We will test this hypothesis during a three phase protocol: phase 1 is a 5 to 7 day inpatient phase to induce abstinence and perform baseline stress-sensitivity testing. Phase 2 is a 4 week outpatient, randomized, double-blind, placebo-controlled phase during which patients attend the clinic 3x/week for medication (mifepristone 600 mg vs. placebo), medical monitoring, therapy, and toxicology testing. Phase 3 is a 4 week follow-up outpatient phase similar to phase 2, but without medication intake to test the long term effects of mifepristone. Stress sensitivity testing is repeated at the end of phase 3. The primary outcome will be time to relapse to cocaine use (days from end of phase 1), with secondary outcomes being stress sensitivity before and after mifepristone to see if mifepristone's potential effect is mediated through an effect on stress sensitivity. All participants will be genotyped for the Al 18G polymorphism at the 0PRM1 receptor, which, when binding beta endorphin, mediates tonic inhibition of ACTH release at the anterior pituitary. As Al 18G affects beta endorphin binding potency, it may be an important genetic marker of stress sensitivity. PUBLIC HEALTH RELEVANCE: No pharmacological treatments of proven efficacy exist to treat cocaine dependence. As stress is frequently cited as a cause of continued cocaine use, medications that directly affect the brain and body's stress mechanisms could provide new treatments for cocaine and other drug addictions.